Major depressive disorder and substance dependence, respectively, rank among the most significant causes of mortality and disability in the American and worldwide populations (WHO, 2008; CDC, 2005). While major depression and addiction have traditionally been studied as distinct phenomena, intriguing evidence suggests that diametrical impairments in common neurobehavioral affect and motivation systems may underlie the disorders' etiologies and contribute to the high prevalence of substance dependence in depression. Recent advances in functional neuroimaging, coupled with novel analytic methods, and emerging data suggest that a re-conceptualization of the conditions may be warranted. Specifically, key aspects of substance dependence (including nicotine dependence) and major depression may be quantified on extreme ends of axes commonly used to quantify motivated behavior or valuation. In doing so, the pathophysiology underlying the high co- morbidity of major depression with substance dependence may be elucidated and lead to improved diagnostics and therapies for the conditions as they occur separately and together. Thus, the broad goal of this project is to identify and refine a common neurobehavioral space within which anomalies of valuation in depression and nicotine dependence may be understood. We suggest that recent functional neuroimaging data in four domains of motivated behavior provide an initial direction for this work; these areas are: (i) affect/cue reactivity; (ii) reward/loss-guided probabilistic learning; and (iii) responses to counterfactual signals. We believe that these data will facilitate advances in the following areas: a) clarifying the common and distinct neuropathology of motivated behavior in nicotine dependence and depression, and b) providing initial data on neurobehavioral anomalies that contribute to the high prevalence of co-occurring nicotine dependence and depression. PUBLIC HEALTH RELEVANCE: Cigarette smoking and major depressive disorder, respectively, rank among the most significant causes of mortality and disability in the American and worldwide populations (WHO, 2008; CDC, 2005). We believe that these data will facilitate advances in the following areas: a) clarifying the common and distinct neuropathology of motivated behavior in nicotine dependence and depression, and b) providing initial data on neurobehavioral anomalies that contribute to the high prevalence and particularly debilitating effects of co-occurring nicotine dependence and depression. The human and fiscal cost of nicotine dependence and major depression motivates the attempt to identify quantitative neurobehavioral measures that may be used to understand the pathophysiology of the conditions.